Phosphatidylinositol 3-kinases (“PI-3 kinase” or “PI3K”) comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (“PIP”), phosphoinositol-3,4-diphosphate (“PIP2”) and phosphoinositol-3,4,5-triphosphate (“PIP3”) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Human cells contain three genes (PIK3CA, PIK3CB and PIK3CD) encoding the catalytic p110 subunits (α, β, δ isoforms) of class IA PI3K enzymes. These catalytic p110α, p110β, and p110δ subunits are constitutively associated with a regulatory subunit that can be p85α, p55α, p50α, p85β or p55γ. p110α and p110β are expressed in most tissues. Class 1B PI3K has one family member, a heterodimer composed of a catalytic p110γ subunit associated with one of two regulatory subunits, either the p101 or the p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class 1B, as well as p110β in some circumstances, is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of class I PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).
Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110a isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85α that serve to up-regulate the p85-p110 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers, including 32% of colorectal cancers, 27% of glioblastomas, 25% of gastric cancers, 36% of hepatocellular carcinomas, and 18-40% of breast cancers. (Samuels et al., Cell Cycle 3(10):1221 (2004); Hartmann et al, Acta Neuropathol., 109(6):639 (June 2005); Li et al, BMC Cancer 5:29 (March 2005); Lee et al, Oncogene, 24(8):1477 (2005); Backman et al, Cancer Biol. Ther. 3(8): 772-775 (2004); Campbell et al., Cancer Research, 64(21): 7678-7681 (2004); Levine et al., Clin. Cancer Res., 11(8): 2875-2878 (2005); and Wu et al, Breast Cancer Res., 7(5):R609-R616 (2005)). Deregulation of PI3K, including the α-isoform, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).
(S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) is a specific 2-carboxamide cycloamino urea derivative compound that potently and selectively targets the alpha (α)-isoform of class IA PI3K. This compound has the following chemical structure:
(hereinafter, “compound of formula (I)” or “Compound A”). The compound of formula (I) and pharmaceutically acceptable salts thereof, suitable formulations, and its method of preparation are described in PCT Application WO2010/029082.
In a Phase I clinical trial, this alpha-isoform selective PI3K inhibitor compound (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) demonstrated clinical efficacy in the single-agent treatment of patients having advanced solid malignancies carrying an alteration in the PIK3CA gene. In the dose escalation phase, patients were orally administered this compound either (a) at a dosage ranging from 30 mg to 450 mg once per day (q.d.) on a continuous daily schedule for 28-days, or (b) at a dosage ranging from 120 mg to 200 mg twice per day (b.i.d.) on a continuous daily schedule for 28-days, as guided by Bayesian logistic regression model with overdose control. After determination of the maximal tolerated dose (MTD), the dose expansion phase was conducted to additionally treat patients having head and neck cancer with a PIK3CA alteration, patients having solid tumors with PIK3CA alteration, and patients having PIK3CA wildtype ER+/HER2-breast cancer. Clinical efficacy of this compound has been demonstrated preliminarily. As of Feb. 15, 2013, confirmed partial responses have been observed in several patients treated at ≥270 mg/day, including patients suffering from breast cancer (1 patient, confirmed), colorectal cancer (1 patient confirmed), endometrial cancer (1 patient, confirmed) and cervical cancer (1 patient confirmed). (Gonzalez-Angulo et al., “Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: results from the first-in-human study”, Presentation at the 2013 ASCO Annual Meeting, held May 31-Jun. 4, 2013 in Chicago, Ill.)
Despite the clinical efficacy of this compound in this Phase I clinical trial, some patients administered this compound on the once per day or twice per day continuous daily schedule demonstrated at least one side effect or adverse event including, but not limited to, hyperglycemia (49% of patients), nausea (43% of patients), decreased appetite (34% of patients), diarrhea (35% of patients), rash and hypersensitivity (34% of patients), asthenia/fatigue (34% of patients), vomiting, stomatitis, dysgeusia, and/or dyspepsia. (Gonzalez-Angulo et al., Presentation at the 2013 ASCO Annual Meeting, held May 31-Jun. 4, 2013 in Chicago, Ill.)
Currently, there is an unmet need for a potent alpha (α)-isoform selective PI3K inhibitor which can be administered to patients in a dosage or dosage regimen that is clinically effective for treatment of proliferative diseases, particularly cancer, but also that relieves, reduces, or alleviates the any known and unknown side effects (e.g, by severity, occurrence rate, or frequency) of the drug. It is believed that this has not been achieved for any alpha-isoform selective PI3K inhibitor prior to the present invention.